The objective of the current study is to develop a prototype vaccine for the prevention of group A streptococcal pharyngitis. Group A streptococci (GAS) cause a variety of suppurative infections in humans, with, conservatively, 20 million cases of streptococcal pharyngitis in the United States each year. Untreated, streptococcal infection may lead to non-suppurative sequelae, acute rheumatic fever and acute post-streptococcal glomerulonephritis. No effective vaccine to prevent GAS infection currently exists, principally due to the serotypic diversity of the streptococcal M protein (greater than 120 serotypes). Recent studies have identified a region of the M protein, which is conserved among most serotypes associated with rheumatic fever. Preliminary animal data indicates that mucosal delivery of region is protective against heterologous challenge with GAS, emphasizing the potential importance of this region as a vaccine candidate. The goal of the current proposal is to engineer subunit constructs of the M protein conserved region. Subsequent to in vitro characterization studies, the subunits will be used as immunogens in rodent animal experiments to generate protective immunity. Various mucosal formulations will be employed to determine the optimal delivery system for the subunit vaccine in these models, as a prelude to subsequent (Phase II) human trials. PROPOSED COMMERCIAL APPLICATION The proposed research is intended as a direct precursor to human clinical trials and subsequent commercialization of a vaccine for the prevention of group A streptococcal pharyngitis and, as a consequence, rheumatic fever. The current market for such a vaccine is estimated at 300-500 million dollars for a disease which consumes billions of dollars in doctors visits, diagnostic tests, and lost time from work.